Human-Derived CD19 CAR Design to Reduce Immunogenicity
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Solution Overview
Problem
Current anti-CD19 chimeric antigen receptor (CAR) therapies for B-cell malignancies induce significant toxicity and immunogenicity in humans, including elevated serum cytokines and human anti-mouse immune responses due to murine sequences.
Innovation Solution
Development of isolated or purified chimeric antigen receptors (CARs) comprising specific amino acid sequences, including extracellular spacers, transmembrane domains, and intracellular T-cell signaling domains, which are human-derived to reduce toxicity and immunogenicity, and methods for using these CARs to target and destroy malignant B-cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If murine sequences are used in anti-CD19 CAR therapies, then CAR functionality is achieved, but human anti-mouse immune responses and immunogenicity occur
Solution Approach 1:
The patent changes the species origin parameter of the CAR sequences from murine to human. The anti-CD19 CAR comprises human-derived sequences including the single-chain variable fragment (scFv) from human anti-CD19 antibodies, human CD8α transmembrane domain, and human costimulatory domains (CD28, 4-1BB). This parameter change eliminates human anti-mouse immune responses while maintaining CAR functionality.
Solution Approach 2:
The patent creates a composite human-derived CAR structure by combining multiple human sequences: human anti-CD19 scFv, human CD8α transmembrane domain, and human costimulatory domains. This composite approach ensures complete human compatibility across all CAR components, eliminating immunogenicity while preserving therapeutic function.
2Productivity
If current anti-CD19 CAR therapies are administered, then B-cell malignancies are targeted, but significant toxicity occurs due to elevated serum cytokines
Solution Approach 1:
The patent changes the sequence origin parameter from murine to human across all CAR components. Clinical data presented in the patent demonstrates that human-derived CARs significantly reduce cytokine release syndrome toxicity while maintaining anti-B-cell malignancy efficacy. The human sequences are more compatible with human immune system regulation, reducing pathological cytokine elevation.
3Ease of manufacture
If murine-derived CARs are used, then CAR T-cell therapy can be constructed, but the therapy induces human anti-mouse immune responses
Solution Approach 1:
The patent systematically changes the species parameter of all CAR components from murine to human. The constructed CAR comprises entirely human-derived sequences including human anti-CD19 scFv, human CD8α transmembrane domain, and human costimulatory domains. This complete humanization eliminates human anti-mouse immune responses while maintaining ease of CAR T-cell construction through standard transduction methods.
Data Source
AI summary
The invention is directed to a chimeric antigen receptor (CAR) directed against CD19, which comprises an amino acid sequence of any one of SEQ ID NO: 1-SEQ ID NO: 13. The invention also provides T-cells expressing the CAR and methods for destroying malignant B-cells.